Targeting Myeloma Cell-Host Bone Marrow Interactions

在之前的资助阶段，我们专注于确定骨髓(BM)微环境在多发性骨髓瘤(MM)细胞生长、存活和耐药中的作用。重要的是，我们已经成功地将多种针对这些相互作用的新型药物(Bortezomib，来那度胺)从长凳转移到床边，并获得FDA批准用于治疗MM。我们之前的研究主要集中在骨髓环境的细胞成分上，包括成纤维细胞、破骨细胞、成骨细胞和内皮细胞。在这一更新应用中，我们将重点研究浆细胞样树突状细胞(PDC)的作用，主要是 在MM的病理生理学中，我们的数据显示PDCs在MM中是功能失调的，因为它们不能刺激T细胞反应。重要的是，即使在常规药物和新药存在的情况下，它们也能诱导MM细胞的生长和存活。因此，目前的建议试图加强我们对MM细胞与PDCs的细胞间相互作用及其治疗相关性的理解，并具体解决三个相互关联的假设：1)MM细胞的生物学行为受其与PDCs的相互作用调节；2)PDC-MM相互作用的分子和功能后遗症是潜在的治疗靶点；以及3)这些相互作用在体内的聚集相互作用允许合理设计新颖的单一和联合靶向治疗。在这些假设的基础上，目前的提案侧重于一套截然不同、但相互作用和互补的方案。明确的目标。我们建议：确定pDC在MM细胞生长、存活、耐药和体外迁移中的作用(特异性目标1)；识别介导pDC-MM相互作用的分子和细胞机制，并验证它们的功能意义和治疗相关性(特异性目标2)；利用多发性骨髓瘤动物模型在体内验证针对介导pDC-MM相互作用的分子和细胞机制的新疗法(特异性目标3)。总体而言，这些研究将为在MM的新治疗策略中直接靶向pDC或阻断pDC-MM相互作用以增强MM的细胞毒性、克服耐药性和改善患者预后提供基础。

In the previous funding period, we focused on identifying the role of the bone marrow (BM) microenvironment in conferring growth, survival, and drug resistance in multiple myeloma (MM) cells. Importantly, we have successfully translated multiple novel agents (bortezomib, lenalidomide) targeting these interactions from the bench to the bedside and FDA approval for treatment of MM. Our prior studies have focused on the cellular components of BM milieu including fibroblasts, osteoclasts, osteoblasts, and endothelial cells. In this renewal application, we will focus on characterizing the role of plasmacytoid dendritic cells (pDCs), predominantly localized in the MM BM, in the pathophysiology of MM. Our data show that pDCs are dysfunctional in MM, since they do not stimulate T cell responses. Importantly, they induce MM cell growth and survival even in the presence of conventional and novel drugs. The current proposal therefore attempts to enhance our understanding of the intercellular interaction of MM cells with pDCs and its therapeutic relevance, and specifically addresses three inter-related hypotheses: 1) the biological behavior of MM cells is modulated by their interactions with pDCs; 2) the molecular and functional sequelae of pDC-MM interactions represent potential therapeutic targets; and 3) the aggregate interplay of these interactions in vivo allows for the rational design of novel single and combination targeted therapies. Based on these hypotheses, the current proposal focuses on a set of distinct, yet mutually interacting and complementary. Specific Aims. We propose: to characterize the role of pDCs in MM cell growth, survival, drug resistance and migration in vitro (Specific Aim 1); to identify the molecular and cellular mechanisms mediating pDC-MM interactions and validate their functional significance and therapeutic relevance (Specific Aim 2); and to validate novel therapies targeting molecular and cellular mechanisms mediating pDC-MM interactions in vivo using MM animal models for evaluation in phase-I/II clinical trials (Specific Aim 3). Overall, these studies will provide the basis for either directly targeting pDCs or blocking the pDC-MM interaction in novel therapeutic strategies for MM to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.